Boronic acids are transition state analog inhibitors of thrombin and other serine hydrolases. In the 70's, this author and others studied simple alkyl and aryl boronic acids as inhibitors of chymotrypsin & subtilison/1.3. In the 80's, acylboroamino acids, such as acetyl- borophenylalanine, where the boronic acid group replaces the carboxyl group of an amino acid, were prepared by Matteson et al., and studied using chymotrypsin and subtilisin by groups led by Lienhard & Philipp/4.5. More recently, peptide boronic acids have been prepared that show the specificity required for consideration as potential therapeutics. Groups led by Kettner/6 and Katzenellenbogen/7 have prepared oligopeptide boronic acids specific to elastase and chymotrypsin. Kettner and coworkers at DuPont did extensive work on the elastase inhibitors/6 in connection with emphysema. Kettner's group/8 and this group/9.10 have prepared specific inhibitors of thrombin. The thrombin inhibitor prepared by this author and coworkers/9.10 is Z-D- Phe-Pro-methoxypropylboroglycine. This is a potent and highly specific inhibitor of thrombin. Unlike other compounds, it inhibits thrombolytic enzymes such as plasmin or plasminogen activators only weakly. Unlike boroarginine-containing peptides, it has no lethal effect on blood pressure. Transition state analog boropeptide inhibitors are specific probes of enzyme binding sites as seen for transition states. Our previous work has concentrated on boropeptides that contain the oligopeptide on the N-acyl side. Future work in this area will concentrate on boropeptide inhibitors that contain the oligopeptide on the C-terminal side of the inhibitor. These will study a different area of the enzyme binding site and also perhaps lead to biomedically interesting inhibitors. In the proposed project, we will use chemically synthesized peptide libraries of boropeptides, using the approach of Guysen/11. This approach will facilitate the production of boropeptides more specific to thrombin. Success in this approach, which combines transition state analog groups and the generation of peptide libraries, may lead to other enzyme inhibitors interesting for their use in studying enzyme-transition state binding.